Euphorbia humistrata is distributed throughout the Mississippi River valley and along other major river systems in the central and eastern United States. There are scattered reports of this species as a waif or as introduced farther north and/or east (for example, Minnesota, New York, North Carolina, Ontario, South Dakota, and Wisconsin), but the authors have not been able to verify these occurrences. Euphorbia humistrata is similar to E. maculata and is often confused with that species in herbaria. It can be distinguished from E. maculata by its tendency to root at the stem nodes, its longer styles, and its seeds that lack low transverse ridges and that are more bluntly angled. When growing side-by-side, E. humistrata has an overall less congested appearance and its cyathia are not as numerous or crowded as those of E. maculata.